Rufinamide presents an anticonvulsant activity and it is used in epileptics with partial and generalized tonic-clonic convulsions. Its chemical name is 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-carboxamide having the following structure:

Rufinamide was first disclosed by the American patent U.S. Pat. No. 4,789,680 to Ciba-Geigy. Scheme 1 shows the preparation of Rufinamide as described therein. As it is taught, Rufinamide is prepared from intermediate 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid (1H-I) by treatment with thionyl chloride followed by addition of concentrated aqueous ammonia solution. Finally, Rufinamide is recrystallised from ethanol (Scheme 1)

Compound 1H-I is prepared from 2,6-difluorobenzyl azide (IV) and propiolic acid.

The process of Scheme 2, that is, the preparation of intermediate 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid (1H-I), has been found to have several disadvantages like lengthy reaction times and the usage of high boiling point solvents like dimethyl sulfoxide (DMSO).
Zheshan et al. in Progress in Natural Science, 16, 9, 925-929 describe the preparation of 1-substituted benzyl-N-substituted-1,2,3-triazole-4-formamides through reaction of substituted benzyl chloride and sodium azide, subsequent cyclization with ethyl propiolate and, finally, the amidation of the resulting ester derivative (Scheme 2).

The process of Scheme 3 requires high temperatures, long reaction times and the use of a high boiling solvent like DMF. All these aspects are process concerns that must be addressed when considering the process for production in pilot-plant or with manufacturing-scale equipment.
All above processes purify the alkyl azide via distillation or under pressure which are extremely hazardous and can result in explosion.
International patent application WO 2010/043849 describes a process for the preparation of Rufinamide characterized in that no isolation of chemical intermediates is required. The process comprises the reaction between 2,6-difluorobenzylbromide and sodium azide. The solvent reaction is water and the reaction is completed after approximately, 30 hours at 70-75° C. Then, methyl propiolate is added. After the reaction was completed, aqueous ammonia is added to obtain Rufinamide. The formation of 2,6-difluorobenzylazide in the presence of water and at 70-75° C. yields the product after 30 hours of reaction. These conditions are not suitable for large scale production due to the formation of hydrazoic acid which is extremely explosive.
In all these processes, the formation of the triazole ring inevitably produces mixtures of isomers 1H and 3H. However, only the 1H-isomer produces Rufinamide.
There is a need for processes for the preparation of compound 1H-I substantially free of its 3H-isomer that are environmentally friendly, easy to practice, produce high yields of the required product, less costly and that can be adapted to industrial scale. The resulting carboxylic acid derivative will be used to prepare Rufinamide.
On the other hand, European patents EP0994 863 and EP0994864 disclose polymorphic forms of Rufinamide referred as, crystal modification A, A′, B and C. According to the teachings of these patents, crystal modifications A or A′ have better thermodynamic stability than crystal modifications B and C. Crystal modification C, the least stable of the three crystal modifications, can only be obtained under very specific conditions.
However, it has been experimentally found that the crystal modification C is rapidly converted into modification B at room temperature within a few weeks. The modification C is also converted into either the modification A or A′ or into the modification B, depending on experimental conditions. Moreover, the modification A or A′ has a slower dissolution rate in water or in gastric fluid (so-called “slow-release effect”).
One of the most desirable properties of a pharmaceutical compound, which can form different polymorphs (that is the case of Rufinamide), is its solubility in aqueous solution, in particular the solubility of said compound in the gastric juices of a patient. Another important property relates to the ease of processing the polymorphic form into pharmaceutical dosages, as the tendency of a powdered or granulated form to flow as well as the surface properties, determine whether the crystals of said polymorphic form will adhere to each other when compacted into a tablet.
The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product such as improved stability, solubility and/or impurity profile. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.